This discussion addresses renal cell carcinoma (RCC) with one or more
distant metastases. Rarer renal cancers such as renal sarcoma and Wilms
tumor are not considered here.

RCC, which accounts for 85%–90% of renal cancers, has five histologic
types. Clear cell histology, often called conventional RCC, is seen in
80%–85% of RCCs. Papillary cell RCC accounts for another 10%–15% of
RCCs, and the remainder are chromophobe RCC, collecting duct RCC, or
unclassified RCC.

Our discussion includes those RCCs in which the patient presents with a
primary kidney tumor and one or more distant metastases and those in
which the patient has had a previous nephrectomy and now presents with
metastases. In either case, the metastases may occur at one site or be
multifocal, and there may or may not be lymph node involvement because
renal cancers often spread hematologically to distant sites before
involving lymph nodes. The most common sites for distant metastases
from RCC are the lungs and mediastinum, bones, liver, lymph nodes,
adrenal glands, and brain, but metastases may involve any organ.

RCC is amenable to curative surgery if discovered at an early stage,
but unfortunately, a large percentage of patients will require
treatment for advanced disease. According to Eric Jonasch, M.D., an
associate professor in the Department of Genitourinary Medical Oncology
at The University of Texas MD Anderson Cancer Center, 25%–33% of RCC
patients present with metastatic disease, and 20%–40% of patients who
undergo treatment for localized disease will develop metastases later.
“In short, this means that approximately half of patients with RCC will
require treatment for metastatic disease,” he said.

The high incidence of metastatic disease suggests a need for effective
systemic therapies for the initial treatment of patients who have
advanced disease and for adjuvant use in those with lower stage disease
who are at risk of progression. How ever, until recently, few useful
systemic agents had been identified.

Because RCC has proven particularly unresponsive to traditional
(cytotoxic) chemotherapy agents, these are not used in the treatment of
RCC with one exception: patients whose tumors have sarcomatoid features
are treated with gemitabine and doxorubicin or with other agents that
have activity against sarcoma. Any of the histologic subtypes of RCC
may exhibit a component of sarcomatoid differentiation, which is
thought to be a high-grade transformation that portends a more
aggressive course of disease.

For most RCC subtypes, few options were available for the treatment of
metastatic disease or for patients at high risk of developing
metastases until cytokine immunotherapies, notably interleukin-2 (IL-2)
and interferon alfa, emerged in the 1990s. High-dose regimens of IL-2
were found to produce complete remissions in 6%–8% of patients with
metastatic RCC and a cure in 5%. However, high-dose IL-2 is highly
toxic and thus appropriate only for the subset of patients who can
tolerate it and are likely to benefit from it: those with clear cell
histology, good performance status, and a small metastatic burden.
Furthermore, the regimen requires hospitalization and should be
administered only in a center with specialized supportive care.

Interferon alfa produces more modest benefits but has a lower toxicity
profile and is easier to administer than IL-2. Thus, interferon alfa
has been used in more patients and more research protocols than has
IL-2. Because interferon alfa has not demonstrated a survival benefit
over other agents, it is not currently used as a first-line,
single-agent therapy but is used in combination with newer targeted
agents.

A new era in the treatment of metastatic RCC commenced around 2005,
when targeted agents with activity against RCC began to appear. Since
that time, the median survival for patients with metastatic RCC has
increased from 10 months to more than 20 months. The development of
these agents grew out of an increased understanding of RCC pathogenesis
at the molecular level, in particular from the study of the von
Hippel–Lindau tumor suppressor gene (VHL). A challenge for using these
agents is deciding which one to give to a particular patient and how
best to deploy them along with surgical interventions.

Seven targeted agents have been approved by the U.S. Food and Drug
Administration for use in metastatic RCC. Sunitinib, sorafenib,
pazopanib, axitinib, and bevacizumab are antiangiogenic agents
targeting the vascular endothelial growth factor (VEGF) pathway, and
temsirolimus and everolimus are mammalian target of rapamycin (mTOR)
inhibitors. “Whereas conventional cytotoxic chemotherapy targets the
tumor cells, the anti–VEGF agents target the microenvironment—the
milieu in which they grow,” said Nizar M. Tannir, M.D., an associate
professor in and deputy chair of the Department of Genitourinary
Medical Oncology.

The targeted agents are easier to administer (many are oral agents) and
have fewer side effects than traditional immunotherapies. According to
Surena F. Matin, M.D., an associate professor in the Department of
Urology, the advent of these new agents has changed the paradigm for
the treatment of advanced kidney cancers. “The old approach was to
remove the kidney first, even in patients with metastatic disease,” he
said, “but the new classes of medicines available today are changing
that, and we have more options.”

Treatment options

The standard treatment options for patients who present with metastatic
RCC are nephrectomy and metastasectomy, cytoreductive surgery followed
by systemic therapy, or first-line systemic therapy.

The approach for an individual patient is best determined by a
multidisciplinary team in which medical and surgical oncologists
collaborate to weigh the many factors to be considered.

Surgery

Among the first tasks in weighing a patient’s treatment options are to
assess whether the disease is resect able and to determine the
patient’s ability to tolerate surgery. Resectability depends largely on
the location and distribution of primary and metastatic disease. Dr.
Matin said that surgery to excise disease (nephrectomy and
metastasectomy) is a reasonable consideration for a patient whose
disease is primarily in the kidney with a small metastatic
burden—perhaps a solitary metastatic lesion—or for a patient who
presents with a solitary metastasis after a previous nephrectomy.
Conversely, a patient with a small primary tumor and a larger
metastatic burden—perhaps multifocal metastases—is less likely to
benefit from surgery.

Additional considerations can help identify patients who will benefit
from surgery and spare others from an ineffectual operation. The
following risk factors—which were identified in a study led by
Christopher Wood, M.D., a professor in and deputy chair of the
Department of Urology—indicate that surgery is not likely to help, as
survival outcomes are about the same for patients with more than three
of these factors regardless of whether the patients do or do not
undergo surgery:

symptoms from metastases,

elevated lactate dehydrogenase (LDH) levels,

metastases in the liver,

retroperitoneal lymph node involvement,

supradiaphragmatic lymph node involvement, or

a locally advanced primary tumor.

For some patients, nephrectomy may be indicated to alleviate symptoms, notably pain and hematuria.

Patients with potentially resectable primary tumors and multifocal
resectable metastases may benefit from cytoreductive surgery followed
by systemic therapy. Cytoreductive surgery became part of the
therapeutic regimen for metastatic renal cancers with the advent of
immunotherapies in the early 1990s.

According to Dr. Wood, the cytoreductive surgery involves the removal
of as much tumor-bearing tissue as possible, including that at the
primary site, lymph nodes, and metastases.

Studies of cytoreductive surgery followed by immunotherapy showed that
while not all patients benefited, some had a clear survival benefit,
and criteria to select candidates for this treatment emerged. These
criteria are good performance status; the presence of clear cell
histology; the absence of brain, liver, or bone metastases; and the
absence of sarcomatoid features.

Postoperative systemic therapy

Despite the advent of targeted agents, high-dose IL-2 therapy (preceded
by cytoreductive surgery) remains the only known cure for metastatic
RCC. Because of the rigor and toxicity of this treatment course,
however, it must be used judiciously in carefully selected patients.
Although only a small percentage of patients will be able to receive
this treatment, it is important to identify potential candidates before
any other agents are administered because studies indicate that the
benefit is less and the toxicity may be higher for patients who have
received targeted therapies prior to IL-2 than for those who have not.
The selection criteria for IL-2 treatment are a good performance status
without significant comorbidities, clear cell histology, and adequate
risk scores.

The two risk scoring systems most often used by clinicians to direct
RCC therapy are the Memorial Sloan-Kettering Cancer Center (MSKCC) and
the University of California Los Angeles Survival after Nephrectomy and
Immunotherapy scales. The widely used MSKCC risk score takes into
account the patient’s performance status, the length of time from
initial diagnosis of RCC to initiation of therapy, and serum LDH,
hemoglobin, and calcium levels to stratify patients as having
favorable, intermediate, or poor risk. In addition to these factors,
the patient’s attitude toward risk must be addressed and taken into
account when high-dose IL-2 therapy is considered.

For patients who are not candidates for high-dose IL-2 therapy,
postoperative systemic therapy options include the newer targeted
agents.

Dr. Jonasch said that bevacizumab is used in tandem with interferon
alfa, but sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, and
everolimus are currently used singly and sequentially rather than in
combination. Although the idea of using combinations that target more
than one pathway or different parts of a single pathway is logical,
early phase I and II trials indicated that the drugs’ toxicities tend
to be additive, even when drugs with differing toxicity profiles are
used. “Although the ultimate goal of these agents is to be able to
target the molecular profile of each individual tumor and thus truly
personalize treatment, we are not at that point yet,” Dr. Tannir said.
Thus, for now, the choice of which agents to use and how to sequence
them is decided on the basis of tumor histology and the prognostic risk
scores described above.

In general, the antiangiogenic agents appear to be most helpful for
patients in the favorable and intermediate risk groups, and the mTOR
inhibitors have been shown to benefit patients in the poor risk
category. However, the effectiveness of combining cytoreductive surgery
with newer targeted agents in the same manner as IL-2 has yet to be
determined in clinical trials.

First-line systemic therapy

Agents recommended for first-line treatment of metastatic RCCs with
predominantly clear cell histologies include sunitinib, sorafenib,
pazopanib, bevacizumab, and temsirolimus. As clear cell histologies are
the most common, more data about them are available from studies than
for the rarer non–clear cell types. Although some data support the use
of sunitinib, sorafenib, temsirolimus, and erlotinib in the treatment
of non–clear cell RCC, patients with these histologies are currently
best served in clinical trials of experimental agents.

Systemic therapy is indicated as an initial treatment for patients who
do not meet the criteria outlined above for nephrectomy/metastasectomy
or cytoreductive surgery followed by systemic therapy. The group not
meeting the criteria for surgery includes patients who present with a
large metastatic burden or other characteristics that place them in the
poor risk group—a category of patients for whom there were no effective
therapies prior to the development of targeted agents.

In some patients, initial systemic therapy can shrink a large primary
tumor and render it amenable to surgery. Reducing disease burden can
also enhance fitness for surgery in some patients.

Other patients considered for first-line systemic treatment at MD
Anderson are those who have the risk factors listed above that indicate
they would be unlikely to benefit from surgery. “In these instances,
systemic therapy can provide a therapeutically rich period of
observation,” Dr. Jonasch said.

Dr. Tannir explained that giving targeted therapy before nephrectomy
can help determine whether a patient is likely to benefit from surgery.
After receiving systemic therapy, as many as 20% of such patients will
have progressive disease. These patients would not benefit from surgery
and can thus be spared its morbidity. Patients without progressive
disease usually undergo cytoreductive nephrectomy at a time determined
to be optimal for each patient or, in patients treated in clinical
trials, after a fixed number of cycles of a particular agent. “Systemic
therapy is a way of letting the disease declare itself,” he said. MD
Anderson pioneered this approach, which has an additional benefit: “We
can interrogate the tissue eventually removed in surgery to analyze key
pathways and targets and compare them to untreated tissue from
nephrectomy and metastasectomy specimens,” he said. This information
can be used to guide future research and therapy.

Many patients respond to first-line treatment with targeted agents, and
their disease stabilizes. But these agents have not proven curative,
and most patients treated with them will eventually experience disease
progression. “We need to understand more about what determines response
and disease progression,” Dr. Tannir said. “What happens in the tumor
and its microenvironment that causes the drug to cease being
effective?”

Some patients can enjoy years of partial or near-complete remission but
over time develop other health issues related to cumulative toxicities
of therapy. The most common of these issues are nephrotic syndrome and
hypertension. “We need to better understand the mechanisms involved,”
Dr. Tannir said, noting that some of the effects are not simply side
effects but may actually be markers of response to the drugs. “We need
a concerted effort to work with specialists in nephrology, cardiology,
pulmonology, and endocrinology to better understand these complications
and how to manage them.”

Observation

Although observation (without treatment) is not listed among the
standard alternatives for managing RCC, Dr. Tannir said that this is
the wisest initial course for a minority of patients because the
disease must be assessed in the context of a patient’s overall health,
comorbidities, and life expectancy. “This is part of the art of
medicine that cannot be listed in templates or guidelines,” he said.
For example, patients who present after a previous nephrectomy with
small and asymptomatic metastases in the pancreas, lymph nodes, or
lungs may have indolent disease, particularly if an extended period has
elapsed since initial treatment. For such patients—particularly if they
are elderly or have significant comorbidities—the RCC is less likely to
shorten life compared with the comorbid illnesses. For these patients,
treatment may pose unnecessary risk or negatively impact quality of
life and may reasonably be deferred until their disease progresses.

On the horizon

Although recent advances in understanding RCC have resulted in agents
that target the disease at the molecular level, it is not yet possible
to match specific agents to individual histologies in a truly
customized way.

Ongoing studies continue working toward the goal of individualized
therapy. One of the most important initiatives at MD Anderson is the
Sequential Two-Agent Assessment in Renal Cell Carcinoma Therapy (START)
trial. Dr. Tannir is the principal investigator of the study, in which
patients with metastatic clear cell RCC and a prior nephrectomy are
randomly assigned to receive one of six two-agent sequences of
everolimus, bevacizumab, or pazopanib, receiving one of these three
agents up front and a different one when disease progression is noted.
An important part of this trial is the collection of tissue and blood
samples along with functional imaging studies to observe response and
disease progression. “We will learn about the characteristics of
patients who respond and their profile when the disease progresses,”
Dr. Tannir said.

Dr. Tannir pointed out that in the excitement over targeted agents,
less attention has been focused on immunotherapies. But two newly
identified immune pathways (PD1 and CTLA4) and agents that target them
have rekindled interest in immunotherapies.

Finally, although von Hippel–Lindau disease is rare, the study of RCC
associated with the hereditary disease will play a pivotal role in
determining the best sequence of newer agents. Dr. Jonasch explained
that many of the nonhereditary RCCs have a VHL mutation that exists
only in the tumor. In patients with von Hippel–Lindau disease, however,
the mutation can be seen in other cells, such as white blood cells,
which are more amenable to study. Dr. Jonasch said the study of VHL
mutations and the agents that act on their pathways could lead to
better treatments for all patients and help determine the best sequence
of treatment for each individual. Stressing the importance of finding
effective first-line treatments, he said, “You don’t have an infinite
number of times to intervene with kidney cancer.”

Contributing Faculty The University of Texas MD Anderson Cancer Center